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Should Mild Hypertension Be Treated?: Choosing the Middle Course
Symposium on Renal Disease: Controversies
Should Mild Hypertension Be Treated? Choosing the Middle Course
C. Venkata S. Ram, MD.*
There is no uncertainty about the value of treating patients with moderate to severe hypertension. However, there is no clear-cut consensus about the benefit of drug treatment for mild hypertension. Although there is no firm demarcation line to separate mild from moderate hypertension, for the purpose of this discussion I will define mild hypertension as a diastolic blood ,pressure between 90 and 100 mm Hg. Since a large segment of American adults, perhaps close to 40 million (75 per cent of the entire hypertensive population) have mild hypertension, this subject has received considerable attention in terms of its cardiovascular risk and treatment. In order to address the important public health question of whether drug treatment of mild hypertension reduces the various complications, a number of clinical trials have been conducted worldwide and the results have received much publicity. 5, 6, 9,10,18 The findings of these studies, especially from the Hypertension Detection and Follow-up Program (HDFP), have been liberally interpreted to justify the broad-scale drug treatment of hypertension. Because of the potential consequences if such a recommendation were to be applied to the population at large, it is important to analyze this viewpoint and search for hard evidence'to justify routine drug treatment of mild hypertension. At the outset, we should acknowledge the inherent problems in making the "diagnosis" of mild hypertension. There is a wide variability within persons of blood pressure levels measured serially. Thus, taking a single blood pressure reading as a demarcation of normotension from hypertension, particularly of a mild degree, is not valid, as repeatedly pointed out by Sir George Pickering. 15 Sometimes, the blood pressure may fluctuate as much as 100 mm Hg systolic and 60 mm Hg or more diastolic within a few hours. 16 Thus, we should exercise care in diagnosing hypertension, particularly of the mild variety. However, even when sufficient allowance is made for the day-to-day fluctuation in blood pressure levels, the concept of mild hypertension is a valid one; i. e., some people have a diastolic blood *Associ.ate Professor ofInternal Medicine, University of Texas Health Science Center at Dallas; Director, Hypertension Clinics, St. Paul Hospital and Parkland Memorial Hospital, Dallas, Texas
Medical Clinics of North America-Vo!' 68, No. 2, March 1984
469
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pressure consistently between 90 and 100 mm Hg. The challenge, therefore, is how to deal with this vast population which is regarded as important by virtue of prevalence and potential risk of mild hypertension. There are valid reasons why we should agonize over the problem of mild hypertension. First, if mild hypertension is as much a risk factor as is moderate or severe hypertension, then a large portion of the population is exposed to various complications. Second, if drug treatment of mild hypertension does indeed reduce the risk, as has been claimed, then millions of people can derive benefit from modern antihypertensive drug therapy. The question that practicing physicians must ask is whether there is any conclusive proof to rationalize routine drug therapy of mild hypertension. The answer resides in proper analysis of the published trials on mild hypertension.
MILD HYPERTENSION TRIALS Hypertension Detection and Follow-Up Program Of all the mild hypertension trials, the HDFP results have generated the most intense interest in the scientific and lay press. This study represents the largest of its kind to date: approximately 11,000 patients, of whom 8000 had initial diastolic blood pressures between 90 and 104 mm Hg, completed the study, the results of which were analyzed at the end of a five-year period. This trial compared the effectiveness of systematic treatment in special centers (stepped care: the se group) with that of treatment in the general medical community (referred care: the Re group). The se group patients were treated by HDFP personnel. The medications and other services, including transportation, were provided free of charge. The patients were closely monitored and were in regular contact with the staff members of HDFP. In contrast, the Re group (control) patients were treated and followed at usual sources of community medical care. They were not given any incentives and were seen infrequently by their physicians and only four times in five years by the investigators. The results showed the absolute mortality was 6.4 per cent in the se group and 7.7 per cent in the Re group, corresponding to an absolute reduction of 1.3 per cent in the se group. The overall five-year difference in cardiovascular mortality between the two groups was 2.6 per 1000 patient-years of treatment. On the grounds that mortality was less in the se group, some investigators of the HDFP have recommended widespread treatment of mild hypertension. Is it possible to accept such judgments on the basis of HDFP data? In the first place, the se and Re groups cannot be considered comparable. The se participants were beneficiaries of supervised medical care with strong support and rapport provided by full-time, dedicated staff, whereas the Re patients did not receive special favors. Stated simply, the Re patients perhaps represent the real-world practices. A large number of patients in the study were already on some form of antihypertensive therapy and therefore may really have had a higher degree of hypertension and been wrongly allocated to the mild-hypertension group. Also, in this trial,
SHOULD MILD HYPERTENSION BE TREATED?
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death certificates were used to establish the presence or absence of coronary artery disease, which in turn led to the claim of cardioprotection in the se group. To use death certificates as a basis to make a definite claim is unacceptable because of possible misclassification of the causes of death. Further, white women and those under 50 years of age did not benefit from treatment in this study. Thus, there appear to be some problems in the design and conduct of the HDFP trial; the se and Re groups differed in a number of respects, making it difficult to accept the conclusions. Furthermore, the findings were misinterpreted by some. Despite the drawbacks, two important conclusions should be drawn from this trial: (1) mild hypertension is treatable, and (2) carefully supervised systematic medical care may reduce deaths from cardiovascular and noncardiovascular causes. It is doubtful that the difference in diastolic blood pressures between the groups (4.4 mm Hg) alone is responsible for relatively favorable results obtained in the treatment group. Australian Therapeutic Trial in Mild Hypertension In comparison with the HDFP, the Australian Therapeutic Trial in Mild Hypertension had fewer flaws in its design, as the Australian trial included a true placebo group and the profile of the participants was homogenous. The study population had entry diastolic blood pressures between 95 and HO mm Hg. The results were published in two parts: at the end of three years eight months and at the end of four years. At both intervals, the active treatment group had fewer complications than the untreated controls, but this was limited to patients with entry diastolic blood pressures > 100 mm Hg. In patients with diastolic blood pressures < 100 mm Hg, such a difference was not apparent. As in the HDFP study, women and patients under 50 years failed to benefit from treatment. Unfortunately, the Australian trial did not investigate the impact of treatment on patients with diastolic blood pressures between 90 and 95 mm Hg. Even in the studied population, the analysis of results at the end of four years showed a more favorable outcome than at the end of three years eight months, suggesting an instability of the findings. In nearly 78 per cent of patients with initial diastolic blood pressures between 100 and 104 mm Hg, the blood pressure actually fell or stayed the same without drug therapy. The blood pressure rose in the remaining 22 per cent, and it is in this segment that morbidity was concentrated: the patients in whom the blood pressure did not change or fell spontaneously had morbidity similar to that in the treatment group. There were fewer complications in patients whose diastolic blood pressures dropped without drug therapy compared with patients in whom drug treatment induced a comparable fall in the blood pressure (Fig. 1). Thus, there is a seeming paradox-patients treated with drugs had a higher mortality rate! One can argue that hypertension in the treated group was perhaps biologically different, with disparate pathophysiologic sequelae, compared with the placebo group; however, there is no proof for this line of argument, since the groups had identical characteristics and criteria. The Australian trial fails to document any benefit in treating patients with diastolic blood pressures < 100 mm Hg. Two valid and important con-
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COMPLICATIONS IN HYPERTENSIVES TREATED BY PLACEBO VERSUS DRUGS
~ Drug
50 Hypertensive 40 Complications per 1000 Person- 30 Years
•
Placebo
,Average DBP <100 in alll during trial
20 10 95- 99
100-104
105-109
L-Initial Diastolic Blood Pressure-.J
Figure 1. Cardiovascular complications per 1000 person-years among those receiving drugs and those receiving placebo during the Australian trial. Note that for those whose average diastolic pressures were < 100 mm Hg, regardless of initial diastolic blood pressure range, complication rates were lower in those not receiving drugs. More of those from each initial diastolic pressure group who were receiving drugs achieved an end diastolic pressure of <100 mm Hg. The numbers at the top of each column indicate the number of hypertensive complications per 1000 person-years. (From Management Committee: The Australian Therapeutic Trial in Mild Hypertension. Lancet, 1:1261, 1980.)
clusions are warranted from this study: (1) the blood pressure in many mild hypertensives may decline in due course without drug therapy, and (2) antihypertensive therapy reduces the cardiovascular risk in patients with diastolic blood pressures > 100 mm Hg. United States Public Health Service (USPHS) Trial This was a small but straightforward study that compared drug therapy with placebo in patients with uncomplicated hypertension without any apparent additional risk factors. After a seven-year follow-up, patients receiving drug therapy had fewer complications, in the form of electrocardiographic abnormalities. There were no differences in the more serious endpoints such as myocardial infarction and mortality between the treated and untreated groups with mild hypertension (diastolic blood pressure between 90 and 100 mm Hg). This study thus did not show the benefit of treating mild hypertension. Because of the small size of the population studied (390 patients), the results, although valid, cannot be extrapolated to the general population. The Oslo Study This study included men younger than 49 years with diastolic blood pressure < 100 mm Hg who were followed with or without drug therapy for nearly five and one-half years. Results suggest that treatment made no difference despite a reduction of blood pressure by 17/10 mm Hg, a considerably more impressive decline in blood pressure than that obtained in the HDFP study. Sudden deaths (cardiac ?) were more common in the treated group. The morbidity and mortality was concentrated in the group
SHOULD MILD HYPERTENSION BE TREATED?
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of patients in whom the diastolic blood pressure increased to > HO mm Hg. Like the USPHS trial, the Oslo study was of small size and showed no substantive benefit of treating mild hypertension. The Multiple Risk Factor Intervention Trial (MRFIT) The latest study to focus on the issue of mild hypertension is the MRFIT, 12 which was designed to evaluate the effects of modifYing the major cardiovascular risk factors: hypertension, hypercholesterolemia, and cigarette smoking. The data pertaining to mild hypertension yielded surprising results. Patients with initial diastolic blood pressures between 90 and 94 mm Hg who were aggressively treated with antihypertensive drugs had higher mortality and myocardial infarction rates than did those who were less vigorously treated. The observation that patients treated for mild hypertension who had abnormal baseline electrocardiograms had higher coronary death rates is disconcerting. The reasons for this have not yet been analyzed. The MRFIT, however, clearly reaffirms the beneficial effect of treating patients with diastolic blood pressures> 100 mm Hg. REAPPRAISAL OF THE RISK FROM MILD HYPERTENSION Having reviewed the mild hypertension trials, it is critical to place the problem of mild hypertension in a practical perspective, setting aside theoretical expectations. The interpretations and implications of the mild hypertension trials have generated much debate and discussion. 2, 3, 8, 11, 13 In the HDFP, although the se group had fewer complications than the Re group, the benefits appear to be only marginal at best. Even then, the results should not be taken at face value, because the study groups were not comparable in many respects, as already discussed. The risk from mild hypertension was thus unequal, perhaps independent of the blood pressure level itself. The HDFP did not provide a correlation between the blood pressure reduction and the complication rate and outcome. Some patients were already on antihypertensive therapy at the time of entry into the study and thus conceivably could have had a severe form of hypertension. In this category of patients, the benefits of treatment are well demonstrated. 19, 20 Since these patients were considered as mild hypertensives in HDFP, the effectiveness of treatment might have been exaggerated. There was considerable reduction in the noncardiovascular mortality in the se group, attesting to the favorable influence of carefully supervised, systematic free medical care, and it is difficult to credit a 4.4 mm Hg average reduction in diastolic blood pressure as the only mediating factor. In the HDFP, overall five-year mortality in the treatment group was reduced by only 1.3 per cent. In plain words, then, for every 100 patients treated systematicaly by interested teams over a five-year period, 98.7 did not benefit from drug therapy. Should this overwhelming majority be subjected to the cost and inconvenience of routine therapy so that one or two persons may be helped? Given these facts, how many physicians will sincerely enforce the therapy, and how many patients will remain on treatment? I suspect that an appreciable number of physicians and patients will decide against treatment if they know how small the real benefits are.
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The Australian trial showed that drug treatment of patients with diastolic blood pressures > 100 mm Hg is beneficial, a notion that few would dispute. This study reconfirms the fact that mild hypertension may sometimes resolve without drug therapy in many patients. When the treatment was implemented and the blood pressure reduced, the incidence of complications in such patients was higher in comparison with those in whom the blood pressure fell to the same level on placebo (see Fig. 1). One can conclude from this trial that it is illogical to place symptomless mild hypertensive patients on long-term drug therapy without a sufficient waiting period. The MRFIT data should rekindle the critical attitude in some who advocate routine drug therapy for mild, uncomplicated hypertension. The finding in this trial that some patients with mild hypertension treated with drugs had a higher complication rate calls for a critical reappraisal of the problem of mild hypertension. CLINICAL APPROACH TO A PATIENT WITH MILD HYPERTENSION The present uncertainty and differences of opinion regarding mild hypertension leave the practitioner in an ambiguous situation. The mild hypertension trials were undertaken to clarifY the problem, but the results have caused much confusion indeed. It should be clear that all mild hypertension is not alike and the risk from it is not uniform. It has been noted that in uncomplicated, mild hypertension, five-year survival can exceed 97 per cent even when not treated.! A vast majority do not appear to be harmed by mild hypertension. How do you decide, then, to treat or not to treat? Before embarking on drug therapy for patients with diastolic blood pressure < 100 mm Hg, the following factors must be considered: the course of hypertension over a 6 to 12 month period and the presence or absence of other risk factors such as hypercholesterolemia, cigarette smoking, a family history of cardiovascular disease or complications, and, perhaps, the sex of the patient. For patients with diastolic blood pressure < 100 mm Hg, non-drug therapies, such as weight reduction or salt restriction should be tried first. If the diastolic blood pressure remains > 100 mm Hg, drug therapy must be instituted. Even when drug therapy is contemplated, however, non-drug approaches must be included, although compliance with the latter is not likely to be optimal. In mild hypertension, it is advisable to defer drug therapy for a period of 6 to 12 months or longer. These people must be under long-term surveillance. The direction of the blood pressure should be the guide to dictate drug therapy. The blood pressure rarely shoots up suddenly; if it rises, it does so insidiously. Time is on the physician's side for monitoring and assessing the blood pressure level periodically. If, during the observation period, the diastolic blood pressure is rising to a level of 100 mm Hg or more, treatment should be considered. In patients who have other risk factors, perhaps treatment is worthwhile if the pressure does not fall without intervention. Of course, the other risk factors must also be modified if possible.
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The presence of other risk factors argues for drug treatment even in mild hypertension. For example, it has been shown that treated hypertensive patients who continue to smoke have a higher mortality rate than nonsmokers,l yet in one survey, only one third of hypertensive patients were advised by their physicians to stop smoking. 17 If the treatment of hypertension is to prove successful, we ought to tell our patients to stop smoking. As a matter of fact, the risk for a patient with mild hypertension who does not smoke and does not have hyperlipoproteinemia is similar to that for the general population. 7 In summary, the problem of mild hypertension has received much needed attention and scrutiny. While I feel that the available data have not shown a clear-cut benefit of treating all patients with diastolic blood pressure < 100 mm Hg, they should stimulate additional clinical research to identify patients with mild hypertension who are at an increased risk. It is hoped that the ongoing British Medical Research Council Study will provide answers to unsettled queries on mild hypertension, including the benefit:risk analysis of drug treatment. To prescribe drugs on the basis of the height of mercury column alone is to ignore the heterogeneity of mild hypertension. Also, we should not forget the possible psychological implications of placing an asymptomatic patient on life-long therapy, the benefits of which are not well documented. For example, increased absenteeism from work has been reported among newly diagnosed hypertensive patients. 4 Unless we can identify the patients within the stratum of mild hypertension who may get into trouble, large-scale routine treatment must be avoided. We should resolve the unsettled issues without undue delay. Otherwise, very soon we will have to deal with persons who may be labelled "sub-mild hypertensives;" i.e., diastolic blood pressures < 90 mm Hg! It has been shown recently that ambulatory blood pressures may be more important than office blood pressures in determining the clinical course. l4 This finding should serve to reinforce the caution that must prevail in basing therapeutic decisions on casual blood pressure measurements, particularly when faced with a mild elevation in the blood pressure. If antihypertensive therapy is entirely safe, one can perhaps argue for routine treatment of mild hypertension at the psychological and financial impact of converting 40 million people into "patients." From a realistic perspective, we need the means to discriminate among patients with mild hypertension those who are at an increased risk, thus requiring vigorous therapy, those in whom the risk is so minimal that therapy is unjustified, and those who are at no risk at all. Until such crucial information is available, lumping a large segment of our population together on the basis of a biophysical abnormality and recommending routine drug treatment on that basis is unwarranted. REFERENCES l. Bulpitt, C. J.: Prognosis of treated hypertension 1951-198l. Br. J. Clin. Pharmacol., 13:73, 1982. 2. Freis, E. D.: Should mild hypertension be treated? N. Engl. J. Med., 307:306, 1982.
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3. Gifford, R W.: Mild hypertension: Should it be treated? Postgrad. Med., 70:19, 1982. 4. Haynes, R B., Sackett, D. L., Taylor, W., et al.: Increased absenteeism from work after detection and labelling of hypertensive patients. N. Engl. J. Med., 299:741, 1978. 5. Helgeland, A.: Treatment of mild hypertension-A five-year controlled drug trial: The Oslo study. Am. J. Med., 69:725, 1980. 6. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the Hypertension Detection and Follow-up Program: Reduction in mortality of persons with high blood pressure, including mild hypertension. J.A.M.A., 242:2562,1979. 7. Kannel, W. B., and Dawber, T. R.: Hypertension as an ingredient of a cardiovascular risk profile. Br. J. Hosp. Med., 2:508, 1974. 8. Kaplan, N. M.: Therapy for mild hypertension: Toward a more balanced view. J.A.M.A., 249:365, 1983. 9. Management Committee of the Australian Hypertension Trial: Initial results of the Australian Therapeutic Trial in Mild Hypertension. Clin. Sci., 57:449S, 1979. 10. Management Committee of the Australian Therapeutic Trial in Mild Hypertension: Untreated mild hypertension. Lancet, 1:185, 1982. 11. Moser, M.: "Less severe" hypertension: Should it be treated? Am. Heart J., 101:465, 1982. 12. Multiple Risk Factor Intervention Trial Research Group: Multiple risk factor intervention trial: Risk factor changes and mortality results. J.A.M.A., 248:1465, 1982. 13. Peart, W. S.: The problem of treatment in mild hypertension. Clin. Sci., 61 :403S, 1981. 14. Perloff, D., Sokolow, M., and Cowan, R: The prognostic value of ambulatory blood pressures. J.A.M.A., 249:2792, 1983. 15. Pickering, G. W.: High Blood Pressure. Edition 2. New York, Grune and Stratton, Inc., 1968. 16. Pickering, G. W.: Hypertension: Natural histories and consequences. In Laragh, J. H. (ed.): Hypertension Manual: Mechanisms, Methods, Management. New York, DunDonnelly Publ. Corp., 1975, pp. 3-30. 17. Public Health Service: Health United States 1980 (with prevention profile). Washington, D.C., Government Printing Office, DHHS Publication No. (PHS)81-1232, 1981, p. 37. 18. Smith, W. M.: Treatment of mild hypertension: Results of a ten-year intervention trial. Circ. Res., 40:198, 1977. 19. Veterans Administrative Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. J.A.M.A., 202:1028, 1967. 20. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. J.A.M.A., 213:1143, 1970. Hypertension Division Department of Internal Medicine University of Texas Health Science Center at Dallas 5323 Harry Hines Boulevard Dallas, Texas 75235
Should Mild Hypertension Be Treated? Choosing the Middle Course
C. Venkata S. Ram, MD.*
There is no uncertainty about the value of treating patients with moderate to severe hypertension. However, there is no clear-cut consensus about the benefit of drug treatment for mild hypertension. Although there is no firm demarcation line to separate mild from moderate hypertension, for the purpose of this discussion I will define mild hypertension as a diastolic blood ,pressure between 90 and 100 mm Hg. Since a large segment of American adults, perhaps close to 40 million (75 per cent of the entire hypertensive population) have mild hypertension, this subject has received considerable attention in terms of its cardiovascular risk and treatment. In order to address the important public health question of whether drug treatment of mild hypertension reduces the various complications, a number of clinical trials have been conducted worldwide and the results have received much publicity. 5, 6, 9,10,18 The findings of these studies, especially from the Hypertension Detection and Follow-up Program (HDFP), have been liberally interpreted to justify the broad-scale drug treatment of hypertension. Because of the potential consequences if such a recommendation were to be applied to the population at large, it is important to analyze this viewpoint and search for hard evidence'to justify routine drug treatment of mild hypertension. At the outset, we should acknowledge the inherent problems in making the "diagnosis" of mild hypertension. There is a wide variability within persons of blood pressure levels measured serially. Thus, taking a single blood pressure reading as a demarcation of normotension from hypertension, particularly of a mild degree, is not valid, as repeatedly pointed out by Sir George Pickering. 15 Sometimes, the blood pressure may fluctuate as much as 100 mm Hg systolic and 60 mm Hg or more diastolic within a few hours. 16 Thus, we should exercise care in diagnosing hypertension, particularly of the mild variety. However, even when sufficient allowance is made for the day-to-day fluctuation in blood pressure levels, the concept of mild hypertension is a valid one; i. e., some people have a diastolic blood *Associ.ate Professor ofInternal Medicine, University of Texas Health Science Center at Dallas; Director, Hypertension Clinics, St. Paul Hospital and Parkland Memorial Hospital, Dallas, Texas
Medical Clinics of North America-Vo!' 68, No. 2, March 1984
469
470
C.
VENKATA
S. RAM
pressure consistently between 90 and 100 mm Hg. The challenge, therefore, is how to deal with this vast population which is regarded as important by virtue of prevalence and potential risk of mild hypertension. There are valid reasons why we should agonize over the problem of mild hypertension. First, if mild hypertension is as much a risk factor as is moderate or severe hypertension, then a large portion of the population is exposed to various complications. Second, if drug treatment of mild hypertension does indeed reduce the risk, as has been claimed, then millions of people can derive benefit from modern antihypertensive drug therapy. The question that practicing physicians must ask is whether there is any conclusive proof to rationalize routine drug therapy of mild hypertension. The answer resides in proper analysis of the published trials on mild hypertension.
MILD HYPERTENSION TRIALS Hypertension Detection and Follow-Up Program Of all the mild hypertension trials, the HDFP results have generated the most intense interest in the scientific and lay press. This study represents the largest of its kind to date: approximately 11,000 patients, of whom 8000 had initial diastolic blood pressures between 90 and 104 mm Hg, completed the study, the results of which were analyzed at the end of a five-year period. This trial compared the effectiveness of systematic treatment in special centers (stepped care: the se group) with that of treatment in the general medical community (referred care: the Re group). The se group patients were treated by HDFP personnel. The medications and other services, including transportation, were provided free of charge. The patients were closely monitored and were in regular contact with the staff members of HDFP. In contrast, the Re group (control) patients were treated and followed at usual sources of community medical care. They were not given any incentives and were seen infrequently by their physicians and only four times in five years by the investigators. The results showed the absolute mortality was 6.4 per cent in the se group and 7.7 per cent in the Re group, corresponding to an absolute reduction of 1.3 per cent in the se group. The overall five-year difference in cardiovascular mortality between the two groups was 2.6 per 1000 patient-years of treatment. On the grounds that mortality was less in the se group, some investigators of the HDFP have recommended widespread treatment of mild hypertension. Is it possible to accept such judgments on the basis of HDFP data? In the first place, the se and Re groups cannot be considered comparable. The se participants were beneficiaries of supervised medical care with strong support and rapport provided by full-time, dedicated staff, whereas the Re patients did not receive special favors. Stated simply, the Re patients perhaps represent the real-world practices. A large number of patients in the study were already on some form of antihypertensive therapy and therefore may really have had a higher degree of hypertension and been wrongly allocated to the mild-hypertension group. Also, in this trial,
SHOULD MILD HYPERTENSION BE TREATED?
471
death certificates were used to establish the presence or absence of coronary artery disease, which in turn led to the claim of cardioprotection in the se group. To use death certificates as a basis to make a definite claim is unacceptable because of possible misclassification of the causes of death. Further, white women and those under 50 years of age did not benefit from treatment in this study. Thus, there appear to be some problems in the design and conduct of the HDFP trial; the se and Re groups differed in a number of respects, making it difficult to accept the conclusions. Furthermore, the findings were misinterpreted by some. Despite the drawbacks, two important conclusions should be drawn from this trial: (1) mild hypertension is treatable, and (2) carefully supervised systematic medical care may reduce deaths from cardiovascular and noncardiovascular causes. It is doubtful that the difference in diastolic blood pressures between the groups (4.4 mm Hg) alone is responsible for relatively favorable results obtained in the treatment group. Australian Therapeutic Trial in Mild Hypertension In comparison with the HDFP, the Australian Therapeutic Trial in Mild Hypertension had fewer flaws in its design, as the Australian trial included a true placebo group and the profile of the participants was homogenous. The study population had entry diastolic blood pressures between 95 and HO mm Hg. The results were published in two parts: at the end of three years eight months and at the end of four years. At both intervals, the active treatment group had fewer complications than the untreated controls, but this was limited to patients with entry diastolic blood pressures > 100 mm Hg. In patients with diastolic blood pressures < 100 mm Hg, such a difference was not apparent. As in the HDFP study, women and patients under 50 years failed to benefit from treatment. Unfortunately, the Australian trial did not investigate the impact of treatment on patients with diastolic blood pressures between 90 and 95 mm Hg. Even in the studied population, the analysis of results at the end of four years showed a more favorable outcome than at the end of three years eight months, suggesting an instability of the findings. In nearly 78 per cent of patients with initial diastolic blood pressures between 100 and 104 mm Hg, the blood pressure actually fell or stayed the same without drug therapy. The blood pressure rose in the remaining 22 per cent, and it is in this segment that morbidity was concentrated: the patients in whom the blood pressure did not change or fell spontaneously had morbidity similar to that in the treatment group. There were fewer complications in patients whose diastolic blood pressures dropped without drug therapy compared with patients in whom drug treatment induced a comparable fall in the blood pressure (Fig. 1). Thus, there is a seeming paradox-patients treated with drugs had a higher mortality rate! One can argue that hypertension in the treated group was perhaps biologically different, with disparate pathophysiologic sequelae, compared with the placebo group; however, there is no proof for this line of argument, since the groups had identical characteristics and criteria. The Australian trial fails to document any benefit in treating patients with diastolic blood pressures < 100 mm Hg. Two valid and important con-
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COMPLICATIONS IN HYPERTENSIVES TREATED BY PLACEBO VERSUS DRUGS
~ Drug
50 Hypertensive 40 Complications per 1000 Person- 30 Years
•
Placebo
,Average DBP <100 in alll during trial
20 10 95- 99
100-104
105-109
L-Initial Diastolic Blood Pressure-.J
Figure 1. Cardiovascular complications per 1000 person-years among those receiving drugs and those receiving placebo during the Australian trial. Note that for those whose average diastolic pressures were < 100 mm Hg, regardless of initial diastolic blood pressure range, complication rates were lower in those not receiving drugs. More of those from each initial diastolic pressure group who were receiving drugs achieved an end diastolic pressure of <100 mm Hg. The numbers at the top of each column indicate the number of hypertensive complications per 1000 person-years. (From Management Committee: The Australian Therapeutic Trial in Mild Hypertension. Lancet, 1:1261, 1980.)
clusions are warranted from this study: (1) the blood pressure in many mild hypertensives may decline in due course without drug therapy, and (2) antihypertensive therapy reduces the cardiovascular risk in patients with diastolic blood pressures > 100 mm Hg. United States Public Health Service (USPHS) Trial This was a small but straightforward study that compared drug therapy with placebo in patients with uncomplicated hypertension without any apparent additional risk factors. After a seven-year follow-up, patients receiving drug therapy had fewer complications, in the form of electrocardiographic abnormalities. There were no differences in the more serious endpoints such as myocardial infarction and mortality between the treated and untreated groups with mild hypertension (diastolic blood pressure between 90 and 100 mm Hg). This study thus did not show the benefit of treating mild hypertension. Because of the small size of the population studied (390 patients), the results, although valid, cannot be extrapolated to the general population. The Oslo Study This study included men younger than 49 years with diastolic blood pressure < 100 mm Hg who were followed with or without drug therapy for nearly five and one-half years. Results suggest that treatment made no difference despite a reduction of blood pressure by 17/10 mm Hg, a considerably more impressive decline in blood pressure than that obtained in the HDFP study. Sudden deaths (cardiac ?) were more common in the treated group. The morbidity and mortality was concentrated in the group
SHOULD MILD HYPERTENSION BE TREATED?
473
of patients in whom the diastolic blood pressure increased to > HO mm Hg. Like the USPHS trial, the Oslo study was of small size and showed no substantive benefit of treating mild hypertension. The Multiple Risk Factor Intervention Trial (MRFIT) The latest study to focus on the issue of mild hypertension is the MRFIT, 12 which was designed to evaluate the effects of modifYing the major cardiovascular risk factors: hypertension, hypercholesterolemia, and cigarette smoking. The data pertaining to mild hypertension yielded surprising results. Patients with initial diastolic blood pressures between 90 and 94 mm Hg who were aggressively treated with antihypertensive drugs had higher mortality and myocardial infarction rates than did those who were less vigorously treated. The observation that patients treated for mild hypertension who had abnormal baseline electrocardiograms had higher coronary death rates is disconcerting. The reasons for this have not yet been analyzed. The MRFIT, however, clearly reaffirms the beneficial effect of treating patients with diastolic blood pressures> 100 mm Hg. REAPPRAISAL OF THE RISK FROM MILD HYPERTENSION Having reviewed the mild hypertension trials, it is critical to place the problem of mild hypertension in a practical perspective, setting aside theoretical expectations. The interpretations and implications of the mild hypertension trials have generated much debate and discussion. 2, 3, 8, 11, 13 In the HDFP, although the se group had fewer complications than the Re group, the benefits appear to be only marginal at best. Even then, the results should not be taken at face value, because the study groups were not comparable in many respects, as already discussed. The risk from mild hypertension was thus unequal, perhaps independent of the blood pressure level itself. The HDFP did not provide a correlation between the blood pressure reduction and the complication rate and outcome. Some patients were already on antihypertensive therapy at the time of entry into the study and thus conceivably could have had a severe form of hypertension. In this category of patients, the benefits of treatment are well demonstrated. 19, 20 Since these patients were considered as mild hypertensives in HDFP, the effectiveness of treatment might have been exaggerated. There was considerable reduction in the noncardiovascular mortality in the se group, attesting to the favorable influence of carefully supervised, systematic free medical care, and it is difficult to credit a 4.4 mm Hg average reduction in diastolic blood pressure as the only mediating factor. In the HDFP, overall five-year mortality in the treatment group was reduced by only 1.3 per cent. In plain words, then, for every 100 patients treated systematicaly by interested teams over a five-year period, 98.7 did not benefit from drug therapy. Should this overwhelming majority be subjected to the cost and inconvenience of routine therapy so that one or two persons may be helped? Given these facts, how many physicians will sincerely enforce the therapy, and how many patients will remain on treatment? I suspect that an appreciable number of physicians and patients will decide against treatment if they know how small the real benefits are.
474
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The Australian trial showed that drug treatment of patients with diastolic blood pressures > 100 mm Hg is beneficial, a notion that few would dispute. This study reconfirms the fact that mild hypertension may sometimes resolve without drug therapy in many patients. When the treatment was implemented and the blood pressure reduced, the incidence of complications in such patients was higher in comparison with those in whom the blood pressure fell to the same level on placebo (see Fig. 1). One can conclude from this trial that it is illogical to place symptomless mild hypertensive patients on long-term drug therapy without a sufficient waiting period. The MRFIT data should rekindle the critical attitude in some who advocate routine drug therapy for mild, uncomplicated hypertension. The finding in this trial that some patients with mild hypertension treated with drugs had a higher complication rate calls for a critical reappraisal of the problem of mild hypertension. CLINICAL APPROACH TO A PATIENT WITH MILD HYPERTENSION The present uncertainty and differences of opinion regarding mild hypertension leave the practitioner in an ambiguous situation. The mild hypertension trials were undertaken to clarifY the problem, but the results have caused much confusion indeed. It should be clear that all mild hypertension is not alike and the risk from it is not uniform. It has been noted that in uncomplicated, mild hypertension, five-year survival can exceed 97 per cent even when not treated.! A vast majority do not appear to be harmed by mild hypertension. How do you decide, then, to treat or not to treat? Before embarking on drug therapy for patients with diastolic blood pressure < 100 mm Hg, the following factors must be considered: the course of hypertension over a 6 to 12 month period and the presence or absence of other risk factors such as hypercholesterolemia, cigarette smoking, a family history of cardiovascular disease or complications, and, perhaps, the sex of the patient. For patients with diastolic blood pressure < 100 mm Hg, non-drug therapies, such as weight reduction or salt restriction should be tried first. If the diastolic blood pressure remains > 100 mm Hg, drug therapy must be instituted. Even when drug therapy is contemplated, however, non-drug approaches must be included, although compliance with the latter is not likely to be optimal. In mild hypertension, it is advisable to defer drug therapy for a period of 6 to 12 months or longer. These people must be under long-term surveillance. The direction of the blood pressure should be the guide to dictate drug therapy. The blood pressure rarely shoots up suddenly; if it rises, it does so insidiously. Time is on the physician's side for monitoring and assessing the blood pressure level periodically. If, during the observation period, the diastolic blood pressure is rising to a level of 100 mm Hg or more, treatment should be considered. In patients who have other risk factors, perhaps treatment is worthwhile if the pressure does not fall without intervention. Of course, the other risk factors must also be modified if possible.
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The presence of other risk factors argues for drug treatment even in mild hypertension. For example, it has been shown that treated hypertensive patients who continue to smoke have a higher mortality rate than nonsmokers,l yet in one survey, only one third of hypertensive patients were advised by their physicians to stop smoking. 17 If the treatment of hypertension is to prove successful, we ought to tell our patients to stop smoking. As a matter of fact, the risk for a patient with mild hypertension who does not smoke and does not have hyperlipoproteinemia is similar to that for the general population. 7 In summary, the problem of mild hypertension has received much needed attention and scrutiny. While I feel that the available data have not shown a clear-cut benefit of treating all patients with diastolic blood pressure < 100 mm Hg, they should stimulate additional clinical research to identify patients with mild hypertension who are at an increased risk. It is hoped that the ongoing British Medical Research Council Study will provide answers to unsettled queries on mild hypertension, including the benefit:risk analysis of drug treatment. To prescribe drugs on the basis of the height of mercury column alone is to ignore the heterogeneity of mild hypertension. Also, we should not forget the possible psychological implications of placing an asymptomatic patient on life-long therapy, the benefits of which are not well documented. For example, increased absenteeism from work has been reported among newly diagnosed hypertensive patients. 4 Unless we can identify the patients within the stratum of mild hypertension who may get into trouble, large-scale routine treatment must be avoided. We should resolve the unsettled issues without undue delay. Otherwise, very soon we will have to deal with persons who may be labelled "sub-mild hypertensives;" i.e., diastolic blood pressures < 90 mm Hg! It has been shown recently that ambulatory blood pressures may be more important than office blood pressures in determining the clinical course. l4 This finding should serve to reinforce the caution that must prevail in basing therapeutic decisions on casual blood pressure measurements, particularly when faced with a mild elevation in the blood pressure. If antihypertensive therapy is entirely safe, one can perhaps argue for routine treatment of mild hypertension at the psychological and financial impact of converting 40 million people into "patients." From a realistic perspective, we need the means to discriminate among patients with mild hypertension those who are at an increased risk, thus requiring vigorous therapy, those in whom the risk is so minimal that therapy is unjustified, and those who are at no risk at all. Until such crucial information is available, lumping a large segment of our population together on the basis of a biophysical abnormality and recommending routine drug treatment on that basis is unwarranted. REFERENCES l. Bulpitt, C. J.: Prognosis of treated hypertension 1951-198l. Br. J. Clin. Pharmacol., 13:73, 1982. 2. Freis, E. D.: Should mild hypertension be treated? N. Engl. J. Med., 307:306, 1982.
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3. Gifford, R W.: Mild hypertension: Should it be treated? Postgrad. Med., 70:19, 1982. 4. Haynes, R B., Sackett, D. L., Taylor, W., et al.: Increased absenteeism from work after detection and labelling of hypertensive patients. N. Engl. J. Med., 299:741, 1978. 5. Helgeland, A.: Treatment of mild hypertension-A five-year controlled drug trial: The Oslo study. Am. J. Med., 69:725, 1980. 6. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the Hypertension Detection and Follow-up Program: Reduction in mortality of persons with high blood pressure, including mild hypertension. J.A.M.A., 242:2562,1979. 7. Kannel, W. B., and Dawber, T. R.: Hypertension as an ingredient of a cardiovascular risk profile. Br. J. Hosp. Med., 2:508, 1974. 8. Kaplan, N. M.: Therapy for mild hypertension: Toward a more balanced view. J.A.M.A., 249:365, 1983. 9. Management Committee of the Australian Hypertension Trial: Initial results of the Australian Therapeutic Trial in Mild Hypertension. Clin. Sci., 57:449S, 1979. 10. Management Committee of the Australian Therapeutic Trial in Mild Hypertension: Untreated mild hypertension. Lancet, 1:185, 1982. 11. Moser, M.: "Less severe" hypertension: Should it be treated? Am. Heart J., 101:465, 1982. 12. Multiple Risk Factor Intervention Trial Research Group: Multiple risk factor intervention trial: Risk factor changes and mortality results. J.A.M.A., 248:1465, 1982. 13. Peart, W. S.: The problem of treatment in mild hypertension. Clin. Sci., 61 :403S, 1981. 14. Perloff, D., Sokolow, M., and Cowan, R: The prognostic value of ambulatory blood pressures. J.A.M.A., 249:2792, 1983. 15. Pickering, G. W.: High Blood Pressure. Edition 2. New York, Grune and Stratton, Inc., 1968. 16. Pickering, G. W.: Hypertension: Natural histories and consequences. In Laragh, J. H. (ed.): Hypertension Manual: Mechanisms, Methods, Management. New York, DunDonnelly Publ. Corp., 1975, pp. 3-30. 17. Public Health Service: Health United States 1980 (with prevention profile). Washington, D.C., Government Printing Office, DHHS Publication No. (PHS)81-1232, 1981, p. 37. 18. Smith, W. M.: Treatment of mild hypertension: Results of a ten-year intervention trial. Circ. Res., 40:198, 1977. 19. Veterans Administrative Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. J.A.M.A., 202:1028, 1967. 20. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. J.A.M.A., 213:1143, 1970. Hypertension Division Department of Internal Medicine University of Texas Health Science Center at Dallas 5323 Harry Hines Boulevard Dallas, Texas 75235